WO2009015561A1 - Utilisation de léonurine et compositions - Google Patents

Utilisation de léonurine et compositions Download PDF

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Publication number
WO2009015561A1
WO2009015561A1 PCT/CN2008/001409 CN2008001409W WO2009015561A1 WO 2009015561 A1 WO2009015561 A1 WO 2009015561A1 CN 2008001409 W CN2008001409 W CN 2008001409W WO 2009015561 A1 WO2009015561 A1 WO 2009015561A1
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WIPO (PCT)
Prior art keywords
acid
motherwort
preparation
compound
pharmaceutically acceptable
Prior art date
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PCT/CN2008/001409
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English (en)
Chinese (zh)
Inventor
Yizhun Zhu
Xinhua Liu
Yichun Zhu
Aijun Hou
Xun Sun
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Fudan University
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Priority to EP08783598.9A priority Critical patent/EP2184063B1/fr
Priority to JP2010518479A priority patent/JP5680412B2/ja
Publication of WO2009015561A1 publication Critical patent/WO2009015561A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention belongs to the field of medical technology.
  • the present invention relates to the use of a motherwort compound or a pharmaceutically acceptable salt thereof or a solvate thereof for the preparation of a medicament for reducing the leakage rate of lactate dehydrogenase; a motherwort compound or a pharmaceutically acceptable salt thereof or a solvate thereof Use in the preparation of a medicament for preventing and/or treating acute heart-to-heart infarction or heart failure; and a pharmaceutical composition for preventing and/or treating acute myocardial infarction or heart failure.
  • Chinese herbal medicine Motherwort (Herbaceae, Herba Leonuri, Chinese Motherwort), was first included in the ancient books such as "Shen Nong's Herbal Classic” and “Compendium of Materia Medica”. It has the effect of promoting blood circulation and diuresis and diuresis.
  • the Pharmacopoeia of the People's Republic of China (2000 edition) is used for treatment of irregular menstruation, dysmenorrhea, amenorrhea, endless lochia, edema, edema, acute nephritis and edema.
  • motherwort is one of the main active ingredients of traditional Chinese medicine motherwort, its English name is Leonurine; chemical name is: 4-hydroxy-3, 5-dimethoxy, 4-[(aminoiminomethyl)amino] Butyl benzoate, ⁇ Benzoic acid, 4-hydroxy-3, 5-dimethoxy, 4-[(aminoiminomethyl) amino] butyl ester ⁇ ;
  • the molecular formula is: C 14 3 ⁇ 4iN 3 05;
  • the structural formula is:
  • the molecular weight is: 311.33;
  • melting point 238 ° C decomposition at this temperature
  • soluble in pentanol Nitrite
  • the melting point is 229 ⁇ 230°C, the hydrochloride containing a crystal water, melting point 193 ⁇ 194°C, soluble in cold water, hot water dissolved 1% ⁇ 2%;
  • the toxicity of the motherwort is 0. 4 ⁇ 0. 6g /kg; the MLD of the frog subcutaneous injection of the motherwort is 0. 4 ⁇ 0. 6g / kg;
  • the main sources of the ingredients are: Labiatae var. Leonurussibiricus L. leaves; Motherwort L. heterophyllus Sweet, Artemisia argyi L. artemisia, whole grass.
  • the dose has a linear relationship, and the maximum tension is reached above 2 mg/ml.
  • the motherwort has a bidirectional effect on the specimen of spontaneous contraction.
  • the minimum effective amount or the sudden increase in concentration (more than 5 times the original concentration)
  • High concentrations (greater than 20 mg/ml) are inhibited by local anesthetic effects on the uterine sarcolemma.
  • the uterine contraction of leonurus can last for several hours, but it can be recovered after washing.
  • Atropine 2mg/ml does not affect its contraction.
  • Motherwort A also has a significant excitatory effect on rabbit and cat isolated uterus, but has no effect on rabbit uterus.
  • the low-dose motherwort has an enhanced contraction effect on the isolated frog heart, and it is inhibited when used in a large amount. This inhibition may be due to excitability of the vagus nerve endings.
  • the frog vascular perfusion was performed with the motherwort, which showed vasoconstriction.
  • the degree of shrinkage is proportional to the concentration of the test solution used. Injecting the motherwort (2mg/kg) into the vein of the anesthetized cat, that is, seeing a drop in blood pressure, and recovering after a few minutes. This transient blood pressure drop can still be found after the vagus nerve is cut off.
  • the motherwort is injected, and the blood pressure drops, but it is not as good as the former. Therefore, it can be speculated that the blood pressure lowering effect of the motherwort is not in the vagus nerve center, but may be caused by the excitatory effect on the vagus nerve endings. Motherwort has a significant expansion of blood vessels in warm-blooded animals and has anti-adrenalin effects.
  • a small amount of parenteral base can relax the intestines of the rabbit's intestines, increase the amplitude, and the amplitude becomes smaller and the frequency increases.
  • Rabbits were given intravenous neviator lmg / kg, showing a significant increase in urine output.
  • Motherwort has an arrow-like effect on frog neuromuscular specimens. Motherwort can cause rabbit blood to occlude at a higher concentration.
  • Motherwort can be used as an effective active ingredient, which not only has a good effect of reducing the leakage rate of lactate dehydrogenase and preventing or treating myocardial infarction or heart failure. , and it has quick onset, small side effects and high safety.
  • particillin refers to an optional racemate, a pure stereoisomer, especially an enantiomer or diastereomer of leonurus, or The form of the mixture of stereoisomers in the desired proportions; the “probiotics” forms are in the form of their acids or in the form of their salts, or in the form of their solvates, especially hydrates.
  • the term also includes the individual enantiomers which may be present as their salts or in free form, generally in admixture with less than 5%, preferably less than 2%, especially less than 1%, of another enantiomer. Or a mixture of such enantiomers in any proportion, the mixture of enantiomers comprising a racemic mixture comprising substantially equal amounts of the two enantiomers.
  • the amount of the active ingredient used is the weight of the motherwort or a pharmaceutically acceptable salt thereof or a solvate thereof unless otherwise stated.
  • salt Including acid addition salts, such as hydrochloric acid, sulfuric acid, sodium hydrogen sulfate, sulfurous acid, sodium hydrogen sulfite, nitric acid, phosphoric acid, acetic acid, lactic acid, methanesulfonic acid, lactobionic acid, citric acid, oxalic acid, Glutamate, fumaric acid, maleic acid, aspartic acid, citric acid or succinic acid. These acids are mentioned for illustrative purposes only and are not intended to be limiting.
  • pharmaceutically acceptable carrier refers to those materials which are well known in the art for use as fillers or carrier materials in pills, tablets, capsules and the like. These substances are generally approved by health care professionals for this purpose and as an inactive ingredient of the agent. Compilation of pharmaceutically acceptable carriers and excipients can be found in the Handbook of Pharmaceutical excipients, 2nd edition, Edited by A. Wade and P. J. Weller; American
  • the present invention provides the following technical solutions:
  • the present invention provides the use of a motherwort compound or a pharmaceutically acceptable salt thereof or a solvate thereof for the preparation of a medicament having an effect of reducing the leakage rate of lactate dehydrogenase.
  • the present invention provides a use of a parentergic compound or a pharmaceutically acceptable salt thereof or a solvate thereof for the preparation of a medicament for the prevention and/or treatment of acute cardiac infarction or heart failure.
  • the motherwort compound is a racemate, a pure stereoisomer, especially an enantiomer or a diastereomer of leonurus, or any desired Proportionally mixed stereoisomer mixture;
  • the solvate of the motherwort compound is a hydrate of motherwort.
  • the virgin base compound is pharmaceutically acceptable
  • the salt is an acid addition salt of the motherwort with an acid selected from the group consisting of hydrochloric acid, sulfuric acid, sodium hydrogen sulfate, sulfurous acid, sodium hydrogen sulfite, nitric acid, phosphoric acid, acetic acid, lactic acid, methanesulfonic acid, lactobionic acid, hydrazine. Acid, oxalic acid, glutamic acid, fumaric acid, maleic acid, aspartic acid, citric acid or succinic acid.
  • the pharmaceutical dosage form is selected from the group consisting of: oral preparations, parenteral preparations, topical preparations, inhaled administration preparations, and transdermal preparations.
  • the present invention provides a pharmaceutical composition for preventing and/or treating acute heart; L infarction or heart failure, the pharmaceutical composition comprising: a motherwort compound as an active ingredient or a pharmaceutically acceptable compound thereof a salt or solvate thereof, and one or more pharmaceutically acceptable carriers.
  • the solvate of the motherwort compound is a hydrate of motherwort.
  • the pharmaceutically acceptable salt of the motherwort compound is an acid addition salt of the motherwort and an acid selected from the group consisting of hydrochloric acid, sulfuric acid, sodium hydrogen sulfate, and sub Acid, sodium bisulfite, nitric acid, lithic acid, acetic acid, lactic acid, methanesulfonic acid, lactobionic acid, citric acid, oxalic acid, glutamic acid, fumaric acid, maleic acid, aspartic acid, citric acid or amber acid.
  • an acid selected from the group consisting of hydrochloric acid, sulfuric acid, sodium hydrogen sulfate, and sub Acid, sodium bisulfite, nitric acid, lithic acid, acetic acid, lactic acid, methanesulfonic acid, lactobionic acid, citric acid, oxalic acid, glutamic acid, fumaric acid, maleic acid, aspartic acid, citric acid or amber acid.
  • the pharmaceutical composition is: an oral preparation, a parenteral preparation such as an injection, a topical preparation, an inhalation preparation or a transdermal preparation.
  • the pharmaceutical composition is an oral preparation selected from the group consisting of a tablet, a capsule, a granule, a pill, a drop, a juice or a syrup; preferably,
  • the pharmaceutically acceptable carrier is selected from the group consisting of: disintegrants, lubricants, binders, fillers, solvents, perfumes, sweeteners, antioxidants, surfactants, preservatives, flavoring agents, and coloring agents.
  • compositions of the invention may be prepared by methods well known in the art, preferably in the form of a formulation. Such methods include the step of mixing the active component with a carrier which comprises one or more accessory ingredients.
  • auxiliary components include those commonly used in the art, such as fillers, binders, thinners, disintegrants, lubricants, colorants, flavoring agents, and wetting agents.
  • Formulations suitable for oral administration may be prepared as dispersion units, pellets or granules, as solutions or suspensions, such as pills, tablets or capsules containing a predetermined amount of active ingredient. It is also possible to prepare a formulation for rectal administration as a suppository or enemas.
  • suitable formulations include aqueous and non-aqueous sterile injectables (purity of the active compound ⁇ 90%).
  • Such formulations may be presented in unit dosage form or in the form of multi-dose containers such as sealed vials and ampoules, and such formulations may be lyophilized (lyophilized) in a sterile liquid carrier such as water, such as water, before use. Store under.
  • Formulations suitable for nasal inhalation administration include fine dust or mist which can be produced by metered doses of pressurized aerosols, nebulizers or inhalers.
  • Suitable additives and/or carriers in the context of the present invention are all materials known to the skilled person from the prior art for obtaining herbal preparations.
  • the choice of these carriers and their amount depends on whether the drug is administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, orally or locally.
  • Formulations in the form of tablets, chewable tablets, coated tablets, capsules, granules, drops, juices or syrups are suitable for oral administration, while solutions, suspensions, reconstituted dry preparations and sprays are suitable for parenteral administration. , topical preparation, inhaled administration. It may also be a test for rectal use.
  • the carrier film or patch, optionally in storage form with other agents that promote skin penetration, is an example of a dosage form suitable for transdermal administration.
  • Examples of carriers and additives in oral administration dosage forms are disintegrants, lubricants, binders, fillers, and optionally used include solvents, perfumes, sweeteners, especially carrier materials, diluents, dyes, Antioxidants and more.
  • solvents perfumes, sweeteners, especially carrier materials, diluents, dyes, Antioxidants and more.
  • waxes and fatty acid esters can be used, and for parenterally administered components, carrier materials, preservatives, suspending agents and the like can be used.
  • the amount of active substance administered to the patient will vary as a function of patient weight, mode of administration, and severity of disease.
  • the compounds according to the invention can be released from the formulation in a delayed manner for oral, rectal or transdermal administration.
  • the corresponding sustained release formulations especially once daily once a day, are particularly suitable for the indication according to the invention.
  • the carrier for oral administration of the present invention may be, for example, water, ethanol, dimethylmethanol, glycerol, ethylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, glucose, fructose, lactose, sucrose, syrup , starch, modified starch, gelatin, sorbitol, inositol, mannitol, microcrystalline cellulose, methyl cellulose, carboxymethyl cellulose, cellulose acetate, shellac, cetyl alcohol, polyvinylpyrrolid Pyrrolidone, paraffin, wax, natural rubber and synthetic rubber, gum arabic, alginate, dextran, saturated and unsaturated fatty acids, stearic acid, magnesium stearate, zinc stearate, glyceryl stearic acid Ester, sodium lauryl sulfate, edible oil, sesame oil, coconut oil, peanut oil, soybean oil, lecithin, sodium lactate, polyoxyethylene and propylene
  • the pharmaceutical and pharmaceutical components according to the present invention can be prepared with the aid of known pharmaceutical preparation techniques, such as advanced means, equipment, methods and procedures.
  • a solid preparation such as a tablet
  • the active ingredient of the drug that is, motherwort or a pharmaceutically acceptable salt thereof or a solvate thereof
  • a pharmaceutical carrier for example, a conventional tablet ingredient , for example, corn flour, lactose, sucrose, sorbitol, talc, magnesium stearate, dicalcium phosphate or a pharmaceutically acceptable gum to form a uniformly distributed motherwort or a pharmaceutically acceptable thereof a solid component of a salt or a solvate thereof.
  • Uniform distribution is understood herein to mean that the active ingredient, the parenteral base, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is uniformly distributed throughout the composition, so that it can be readily divided into unit dosage forms having the same activity, such as tablets, pills or Plastic bottles.
  • the solid components are then divided into unit dosage forms.
  • a tablet or pill of a pharmaceutical or pharmaceutical ingredient according to the invention may also be coated or mixed in another component to provide a sustained release dosage form.
  • suitable coating components are a mixture of a polymeric acid and a polymeric acid with materials such as shellac, cetyl alcohol and/or cellulose acetate.
  • compositions of the present invention can be formulated into clinically acceptable dosage forms such as tablets, capsules, granules, oral liquid preparations, subcutaneous administration preparations, suppositories and the like.
  • Oral preparations such as tablets, granules or capsules can be prepared by adding an appropriate amount of the carrier.
  • These dosage forms are prepared according to methods well known to those skilled in the art.
  • the carrier used for the molding process of tablets, granules, capsules, etc. is a commonly used auxiliary agent, such as starch, gelatin, gum arabic, polyethylene glycol, etc., in addition to surfactants, lubricants, disintegrants. , preservatives, flavoring agents, pigments, etc.
  • the above-mentioned motherwort compound of the present invention is subjected to the following in vivo and in vitro experiments, thereby fully verifying the feasibility of the medical use of the present invention:
  • the in vitro experimental study was conducted to examine the effect of leonurus on the amount of LDH leaked out into the culture solution, and the leakage rate of lactate dehydrogenase was measured.
  • Cardiac function and plasma levels of vitamin C and cysteine were detected by ligating the heart failure model of the anterior descending coronary artery.
  • the results showed that the motherwort can reduce ventricular end-systolic pressure, increase the contraction rate, and improve the heart. Function, can increase plasma vitamin C and reduce cysteine content.
  • the experimental results prove that the motherwort can reduce the leakage rate of lactate dehydrogenase, and has a significant effect on preventing and/or treating acute myocardial infarction or heart failure, and can prepare a medicament for preventing acute myocardial infarction or heart failure.
  • Figure 1 is a bar graph showing the lactate (LDH) leakage rate, where the data is expressed as a percentage of the normal group (100%), control indicates no hypoxic group, vehicle indicates hypoxia, losartan Indicated in the losartan group, leonurine in the group treated with leonurus; *: p ⁇ 0.01 compared with the normal group, #: p ⁇ 0.01 compared with the hypoxic group;
  • LDH lactate
  • Figure 2 is a graph showing that motherwort reduces myocardial infarct size, wherein sham indicates a false surgery group, AMI indicates a myocardial infarction group, and Leo 7.5 mg/kg indicates a low dose of motherwort.
  • Leol 5mg/kg means high dose (15mg/kg) of the motherwort; *: Compared with the myocardial infarction group? ⁇ 0.05;
  • Figure 3 is a bar graph showing that natal care reduces the LDH in plasma of rats with myocardial infarction, in which sham is a sham operation group, AMI is a myocardial infarction group, and Leo 7.5 mg.kg- 1 is a low dose of motherwort.
  • Leo mgJcg- 1 was treated with high dose of motherwort (15 mg.kg); *: compared with myocardial infarction group; ⁇ 0.05, #: compared with sham operation group; ⁇ 0.05.
  • Figure 4 is a bar graph showing that motherwort reduces CK in plasma of rats with myocardial infarction, wherein sham represents a sham operation group, AMI represents a myocardial infarction group, and Leo 7.5 mg.kg 4 represents a low dose of motherwort with mg-kg- 1 In the treatment group, Leol 5 mg.kg 4 was treated with high dose of motherwort (mg.kg- 1 ); *: ⁇ ⁇ 0.05 compared with myocardial infarction group, #: and ⁇ - compared with surgery group ⁇ ⁇ 0.05.
  • Figure 5 is a bar graph showing that tryptophan reduces the expression of Bax and increases the mRNA level of Bcl-2, wherein sham represents a sham operation group, AMI represents a myocardial infarction group, and Leo 7.5 mg.kg _1 represents a low dose of motherwort.
  • LeolSmg g was expressed in the high-dose (15 mg.kg _1 ) group of the motherwort; *: compared with the myocardial infarction group; ? ⁇ 0.05, #: compared with the sham-operated group ⁇ 0.05.
  • Figure 6 is a bar graph showing the expression of motherwort minus Bax and increasing the protein level of Bcl-2, wherein sham indicates sham operation group, AMI indicates myocardial infarction group, and Leo 7.5 mg.kg- 1 indicates low dose of motherwort.
  • Leo rngJig- 1 showed a high dose (15 mg.kg -1 ) in the treatment group; *: compared with the myocardial infarction group ⁇ 0.05, #: and ⁇ compared with the surgery group ⁇ 0.05.
  • Example 1 In vitro experiment to examine the effect of leonurus on the leakage rate of lactate dehydrogenase
  • this example used losartan as a positive control drug, and the concentration of the motherwort used was 1 (T 6 mol/L, the experimental data were analyzed by one-way ANOVA, ⁇ 0.01, and the results showed that cell death can be Leading to the leakage of lactase, the amount of leakage of LDH into the culture solution was analyzed by the test, and the results showed that the motherwort could significantly reduce the leakage of lactate dehydrogenase.
  • this embodiment uses the mature heart of the ligature of the anterior descending coronary artery in the field.
  • the infarction model was administered by intraperitoneal injection.
  • the infarct size was detected by TTC staining.
  • the experimental data were analyzed by one-way analysis of variance. Results: ⁇ 0.05, indicating that the motherwort could significantly reduce the myocardial infarct size.
  • Myocardial infarction can cause the release of myocardial enzymes LDH and CK into the plasma, which can significantly reduce the levels of LDH and CK in plasma and reduce the degree of myocardial damage, one-way analysis of variance, ⁇ ⁇ 0.05.
  • Bax is a pro-apoptotic gene
  • Bcl-2 is an anti-apoptotic gene.
  • the motherwort can significantly reduce the expression of Bax mR A and protein levels, and significantly increase the expression of Bcl-2 mRNA and protein.
  • Example 3 Heart failure model test of leonurus
  • a heart failure model in which the anterior descending coronary artery is ligated in the field is used, and the cardiac function is detected by intra-arterial and ventricular intubation.
  • the results show that the motherwort can reduce the end of ventricular systole. Pressure, increase the rate of contraction, and improve heart function.
  • the content of vitamin C and cysteine in plasma was measured by capillary electrophoresis. The results showed that motherwort could increase plasma vitamin C and decrease cysteine content by one-way variance analysis, p ⁇ 0.05.
  • Table 1 shows the results of cardiac function in heart failure models, showing that motherwort improves cardiac function in rats with myocardial infarction, where *: compared with heart failure group p ⁇ 0.05, #: compared with sham operation group ⁇ 0.05.
  • Table 2 shows the results of the test of parentergic to increase vitamin C and cysteine in plasma, where *: compared with heart failure group ⁇ 0.05, **: compared with heart failure group /? ⁇ 0.01, #: ⁇ - Compared to the surgery group? ⁇ 0.05.
  • vitamin c Ascorbic acid (vitamin c), 26.02 ⁇ 3.95**

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Abstract

La présente invention concerne l'utilisation de léonurine ou de sels ou solvates acceptables pharmaceutiquement de léonurine dans la fabrication de médicaments pour diminuer une fuite de LDH, l'utilisation de léonurine ou de sels ou solvates acceptables pharmaceutiquement de léonurine dans la fabrication de médicaments destinés à prévenir et/ou traiter une insuffisance cardiaque ou un infarctus aigu du myocarde, ainsi qu'une composition pharmaceutique destinée à prévenir et/ou traiter un infarctus du myocarde aigu ou une insuffisance cardiaque.
PCT/CN2008/001409 2007-08-02 2008-08-01 Utilisation de léonurine et compositions WO2009015561A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP08783598.9A EP2184063B1 (fr) 2007-08-02 2008-08-01 Utilisation de léonurine pour le traitement de l' insuffisance cardiaque
JP2010518479A JP5680412B2 (ja) 2007-08-02 2008-08-01 レオヌリンの使用およびその組成物

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CN200710044524 2007-08-02
CN200710044524.0 2007-08-02

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US (1) US20090036527A1 (fr)
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WO (1) WO2009015561A1 (fr)

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CN105997975A (zh) * 2016-05-23 2016-10-12 南开大学 益母草碱在制备治疗血管性痴呆药物中的用途
CN106619602B (zh) * 2017-01-23 2019-05-10 南京医科大学 益母草碱的用途
CN111588712A (zh) * 2019-02-21 2020-08-28 复旦大学 益母草碱及其晶体在制备抗高同型半胱氨酸血症药物中的用途
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See also references of EP2184063A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102134210A (zh) * 2010-01-22 2011-07-27 复旦大学 益母草碱衍生物及其制备方法
CN102134210B (zh) * 2010-01-22 2014-03-05 复旦大学 益母草碱衍生物及其制备方法

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EP2184063A1 (fr) 2010-05-12
JP5680412B2 (ja) 2015-03-04
JP2010535159A (ja) 2010-11-18
US20090036527A1 (en) 2009-02-05
EP2184063B1 (fr) 2017-01-18
CN101357125B (zh) 2012-02-08
CN101357125A (zh) 2009-02-04
EP2184063A4 (fr) 2013-11-13

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